ANALYSIS OF FGF23, GALNT3, SAMD9, AND KL GENES IN SCLERODERMA PATIENTS WITH CUTANEOUS CALCINOSIS VE Mitchell. Charlene Williams, Department of Medicine, Center for Translational Medicine, Thomas Jefferson University, Philadelphia, PA.
Scleroderma is a chronic disease characterized by large deposits of collagen (fibrosis) in the skin or other organs. In some cases, the skin fibrosis in scleroderma patients is accompanied by calcinosis, the deposition of calcium-containing crystals in the fingers and around joints and bony surfaces. Another connective tissue disorder displaying abnormal calcification of soft tissues is tumoral calcinosis. Tumoral calcinosis is an uncommon metabolic disorder characterized by massive calcium deposits in the skin and around joints and, in most cases, hyperphosphatemia. Studies have shown that the genetic basis of tumoral calcinosis is inactivating mutations in the genes encoding fibroblast growth factor 23 (FGF23), Klotho (KL), and GalNAc transferase 3 (GALNT3). Sterile Alpha Motif Domain 9 or SAMD9 has also been linked to the disease in patients who do not display hyperphosphatemia. We performed mutational analysis for FGF23, GALNT3, SAMD9, and KL for six patient samples with scleroderma, four of whom had calcinosis. We did not observe any sequence variants in the patients that had not been previously reported as polymorphisms in large population studies. We also observed no significant differences in the expression of GALNT3 and SAMD9 in any of the scleroderma patients as determined by real-time PCR of cDNA prepared from RNA isolated from patients’ fibroblasts. However, we did observe a significant decrease in the expression of FGF23 in all four scleroderma patients who suffered from calcinosis in comparison to those scleroderma patients that did not display calcinosis. The low levels of expression of FGF23 are reminiscent of the decreased levels of circulating FGF23 in tumoral calcinosis patients who harbor loss-of-function mutations in the gene. One calcinosis patient in particular had very low expression of FGF23 and a concomitantly high level of expression of KL, which is believed to be a co-factor in the interaction between FGF23 and the FGF receptor. FGF23 is primarily expressed by bone however, it is also expressed to a lesser extent in many tissues, including skin. Our data suggest that FGF23, and its cognate receptor co-factor, KL, may play important roles in the development of calcinosis in scleroderma patients.
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